We included the patient in the placebo group who died before treatment
in our intent-to-treat analysis. Of the 1026 ineligible patients, 65% were
men, and had a mean (SD) age of 59 (16) years and a Simplified Acute Physiology
Score II (SAPS II) score of 60 (23). Of those randomized, 67% were men and
had a mean (SD) age of 61 (16) years and a SAPS II score of 59 (19).

Figure 2. Kaplan-Meier Analysis of the Probability
of Survival of Patients With Septic Shock

Results are according to the response to the short corticotropin
test. In nonresponders, the median time to death was 12 days in the placebo
and 24 days in the corticosteroid groups; in responders, 14 days in the placebo
and 16.5 days in the corticosteroid groups; and in all patients, 13 days in
the placebo and 19.5 in the corticosteroid groups.

Figure 3. Kaplan-Meier analysis of the Probability
of Continuation of Vasopressor Therapy of Patients With Septic Shock

Results are according to the response to the short corticotropin
test. In nonresponders, the median time to vasopressor therapy withdrawal
was 10 days in the placebo and 7 days in the corticosteroid groups; in responders,
7 days in the placebo and 9 days in the corticosteroid groups; and in all
patients, 9 days in the placebo and 7 days in the corticosteroid groups.

Results One patient from the corticosteroid group was excluded from analyses
because of consent withdrawal. There were 229 nonresponders to the corticotropin
test (placebo, 115; corticosteroids, 114) and 70 responders to the corticotropin
test (placebo, 34; corticosteroids, 36). In nonresponders, there were 73 deaths
(63%) in the placebo group and 60 deaths (53%) in the corticosteroid group
(hazard ratio, 0.67; 95% confidence interval, 0.47-0.95; P = .02). Vasopressor therapy was withdrawn within 28 days in 46 patients
(40%) in the placebo group and in 65 patients (57%) in the corticosteroid
group (hazard ratio, 1.91; 95% confidence interval, 1.29-2.84; P = .001). There was no significant difference between groups in responders.
Adverse events rates were similar in the 2 groups.

Conclusion In our trial, a 7-day treatment with low doses of hydrocortisone and
fludrocortisone significantly reduced the risk of death in patients with septic
shock and relative adrenal insufficiency without increasing adverse events.

Severe sepsis remains an important cause of death, accounting for 9.3%
of all deaths in the United States in 1995.1
If our understanding of the mechanisms of host response to stress has strongly
progressed during the last 2 decades,2 the
various drugs developed for specific targets of the cytokine cascade have
failed to improve patient survival.3,4

Corticosteroids were the first anti-inflammatory drugs tested in randomized
trials. At high doses during short courses, they did not induce favorable
effects.5,6 However, the observation
that severe sepsis may be associated with relative adrenal insufficiency7,8 or systemic inflammation-induced glucocorticoid
receptor resistance9 prompted renewed interest
of a replacement therapy with low doses of corticosteroids during longer periods.10,11

The interest of this new approach was confirmed by the demonstration
that a single intravenous administration of 50 mg of hydrocortisone strongly
improved norepinephrine and phenylephrine mean arterial pressure dose-response
relationships in patients with septic shock,12,13
particularly in those with relative adrenal insufficiency.12
Moreover, 2 small placebo-controlled randomized trials also showed that prolonged
treatment (≥5 days) with low doses of hydrocortisone (about 300 mg daily)
significantly improved the time to vasopressor therapy withdrawal in septic
shock.14,15 Thus, we designed
this placebo-controlled study to assess whether a replacement therapy with
hydrocortisone and fludrocortisone (assuming the possibility of a primary
adrenal insufficiency)16 could improve 28-day
survival in patients with septic shock, with particular interest in patients
with relative adrenal insufficiency.

METHODS

Experimental Design and Study Organization

This placebo-controlled, randomized, double-blind study was performed
on 2 parallel groups at 19 intensive care units (ICUs) in France (Figure 1). It was supported by Groupe d'Etude
et de Recherche sur le Médicament (GERMED), which awarded a grant from
publicly funded resources. The protocol was approved by the Comité
Consultatif de Protection des Personnes dans la Recherche Biomédicale
of Saint-Germain en Laye, France, on February 9, 1995. Inclusions were authorized
from September 11, 1995. Two interim analyses were planned. An independent
main end point and safety monitoring board met after each interim analysis
to decide whether the study should be continued or stopped. Enrollment ended
March 15, 1999. At the end of the study, an independent diagnosis validation
committee blindly classified each patient as being unquestionable, probable,
or nonprobable for having had septic shock.

Patients

All patients 18 years or older and hospitalized in participating ICUs
were prospectively enrolled in the study if they met all the following criteria:
(1) documented site (or at least strong suspicion) of infection, as evidenced
by one or more of the following: presence of polymorphs in a normally sterile
body fluid (except blood), positive culture or Gram stain of a normally sterile
body fluid, clinical focus of infection (eg, fecal peritonitis), wound with
purulent discharge, pneumonia or other clinical evidence of systemic infection
(eg, purpura fulminans); (2) temperature higher than 38.3°C or lower than
35.6°C; (3) heart rate greater than 90 beats per minute; (4) systolic
arterial pressure lower than 90 mm Hg for at least 1 hour despite adequate
fluid replacement and more than 5 µg/kg of body weight of dopamine or
current treatment with epinephrine or norepinephrine; (5) urinary output of
less than 0.5 mL/kg of body weight for at least 1 hour or ratio of arterial
oxygen tension to the fraction of inspired oxygen (PaO2/FIO2) of less than 280 mm Hg; (6) arterial lactate levels higher than 2
mmol/L; and (7) need for mechanical ventilation. Written informed consent
had to be obtained from the patients themselves or their relatives and a short
corticotropin test had to be performed before randomization. Finally, patients
had to be randomized within 3 hours of the onset of shock.

Patients were excluded if they were pregnant or had evidence for acute
myocardial infarction or pulmonary embolism, advanced form of cancer or acquired
immunodeficiency syndrome (AIDS) infection, and contraindication or formal
indication for corticosteroids.

During recruitment, we refined the eligibility criteria by not making
the arterial lactate requirement mandatory (the 6th criterion) but adding
it as an option to the 5th criterion. We also increased the maximum delay
from the onset of septic shock and randomization from 3 to 8 hours (amendment
of July 18, 1996); and we excluded patients who received etomidate during
the 6 hours preceding randomization because it is a selective inhibitor of
the 11 β-hydroxylase and therefore could interfere with cortisol response
to corticotropin (amendment of June 19, 1997).

Randomization

Randomization was centrally performed, concealed, and stratified by
center in blocks of 4 according to a computer-generated random number table.
In each center, sequentially numbered boxes containing the whole treatment
for each patient were delivered to the investigator by the pharmacist following
the order of the randomization list. All patients, medical and nursing staffs,
and pharmacists remained blinded throughout the study period.

Treatments

Hydrocortisone came in vials containing 100 mg of hydrocortisone hemisuccinate
powder and ampoules containing 2 mL of glucose solution solvent, which was
administered intravenously every 6 hours as a 50-mg bolus (Roussel-Uclaf,
Romainville, France). One tablet containing 50 µg of 9-α-fludrocortisone
was administered daily through a nasogastric tube with 10 to 40 mL of water
over 30 seconds (Pharmacie Centrale des Hôpitaux, Paris, France). Placebos
were indiscernible from active treatments. Treatment duration was 7 days.

Data Collection at Inclusion

Clinical Evaluation

The following data were recorded: (1) general characteristics including
estimated prognosis of any underlying disease17
and level of activity limitation18; (2) severity
of illness assessed by vital signs, Simplified Acute Physiology Score II (SAPS
II),19 and Logistic Organ Dysfunction (LOD)
score20; and (3) interventions including the
volume of fluid infusion and the type and doses of vasopressors and antibiotics.

Laboratory Variables

Hematological and chemistry data, arterial lactate and blood gas determinations,
and blood cultures and cultures of specimen drawn from the site of infection
were done systematically. The short corticotropin test was performed using
a 250-µg intravenous bolus of tetracosactrin (Synacthène Ciba,
Rueil-Malmaison, France). Blood samples were taken immediately before the
test and 30 and 60 minutes after the test. After centrifugation, plasma samples
were stored at −80°C until assayed. Cortisol was measured blindly
and serially before interim and final statistical analyses using Immunotech
radioimmunoassay.21 To reduce heterogeneity
in cortisol determination, all plasma samples were measured at a central laboratory.
Cortisol response was defined as the difference between the highest of the
concentrations taken after the test and those taken before the test. Relative
adrenal insufficiency (ie, nonresponders) was defined by a response of 9 µg/dL
or less.7,8

Follow-up

The following data were recorded daily during the 28-day period following
randomization: vital signs, results from standard laboratory tests and cultures
of specimen drawn from any new site of infection, and interventions. In addition,
the patient's status at discharge from ICU and hospital and 1 year after randomization
was recorded.

End Points

The main end point was the 28-day survival distribution from randomization
in nonresponders to the short corticotropin test. Secondary end points were
28-day survival distributions from randomization in responders to the short
corticotropin test and in all patients; 28-day, ICU, hospital, and 1-year
mortality rates; and time to vasopressor therapy withdrawal during the 28
days from randomization in the 2 subsets of patients and in all patients.

A total of 270 patients was the calculated sample size needed to detect,
in a 1-sided test performed with a 0.05 type I error, a difference between
the 2 groups of nonresponders on the 28-day mortality rate of 20% with a 90%
probability, assuming a mortality rate of 95% in the nonresponder placebo
subgroup7,22 and a frequency of
nonresponders of 40% in the population of patients with septic shock.7 A 1-sided formulation was chosen to compute the sample
size because the trial was designed to test whether low doses of corticosteroids
were more effective than placebo, and we had no interest in formally demonstrating
the opposite alternative hypothesis (a deleterious effect of corticosteroids).22,23

The 2 interim analyses were planned using an O'Brien and Fleming stopping
boundary.24 With this procedure, the differences
between the 2 groups were considered significant if the critical z values were higher than 3.471, 2.454, and 2.004 at the first, second,
and final analyses, respectively (corresponding to nominal 2-sided P values <.0005, <.0141 and <.0451, respectively).

The statistical analysis, prospectively defined, was performed according
to the intent-to-treat principle (in all analyses, patients were grouped according
to their original randomized treatment) with SAS statistical software (SAS
Institute, Cary, NC). For continuous variables, the mean (SDs) are reported
whereas, for categorical variables, the number of patients in each category
and the corresponding percentages are given.

Analyses were similarly performed in nonresponders, in responders, and
in all patients. Pretreatment characteristics were compared between groups
using the t test (for continuous variables) or χ2 or Fisher exact tests when appropriate (for categorical variables).
Cumulative event curves (28-day survival and time-to-vasopressor therapy withdrawal
end points) were estimated with the Kaplan-Meier procedure and median times
to event were reported. The effects of treatments on these end points were
estimated from adjusted Cox proportional hazards regression models25 using baseline cortisol, cortisol response, McCabe
classification, LOD score, arterial lactate levels, and PaO2/FIO2 results for the adjustment.8 Corresponding
hazard ratios (HRs) along with their 95% confidence intervals (CIs) were reported.
Proportionality among the event rates in the Cox models was assessed by the
plot of the log (−log [survival function]) vs time. When the proportionality
assumption was not upheld, Cox models were not used and only the Kaplan-Meier
curves were reported along with log-rank tests. For 28-day survival, patients
who were still alive at 28 days were treated as censored. For this end point,
the number needed to treat at 28 days was estimated.26
For time-to-vasopressor-therapy withdrawal, among patients who had more than
1 outcome event during the 28 days from randomization, time to the first event
was used in the analyses. For this end point, the patients who died before
vasopressor therapy could be withdrawn and those for whom vasopressor therapy
could not be withdrawn during the 28 days from randomization were treated
as censored. The effects of treatments on the frequency of fatal events (28-day,
ICU, hospital and 1-year mortality rates) were estimated from logistic regression
analysis using the same variables for the adjustment as the Cox models. Corresponding
adjusted odds ratios (ORs) along with their 95% CIs were reported. We also
computed the 28-day, ICU, hospital, and 1-year relative risks (RRs) of death
along with their 95% CIs. The frequency of adverse events was compared between
groups using the χ2 or Fisher exact tests when appropriate.
All reported P values are 2-sided.

RESULTS

Study Description

From October 9, 1995, to February 23, 1999, 1326 patients were screened
and 300 patients (placebo, 149; corticosteroids, 151) were included in the
study (Figure 1). Interim analyses
were performed on April 3, 1997, and April 20, 1998, after the evaluation
of 114 and 220 patients, respectively. After each analysis, the independent
main end point and safety monitoring board advised the study chairpersons
to continue the study. We included the patient in the placebo group who died
before study drugs could be administered in our intent-to-treat analysis.
One patient in the corticosteroid group was excluded from the final analysis
because of consent withdrawal. Among the 299 remaining patients, there were
229 nonresponders (placebo, 115; corticosteroids, 114) and 70 responders (placebo,
34; corticosteroids, 36).

Characteristics of Study Patients at Inclusion

At baseline, the 2 groups were balanced with respect to general characteristics
(Table 1) and severity of illness
(Table 2). Cortisol response to
corticotropin was higher in the corticosteroid group than in the placebo group
in the all-patients analysis, but the distribution of patients according to
our 3-level prognostic classification8 was
similar in the 2 groups. The type and site of infection and the type of organism
involved were also similar in the 2 groups (Table 3). Finally, a blinded evaluation determined that appropriate
antibiotic therapy, based on the site of infection and available cultures,
was promptly (<24 hours from diagnosis of severe sepsis) started and continued
for at least 7 days in most cases (ie, 95% in the placebo group, 91% in the
corticosteroid group).

Mortality Distribution

Nonresponders

At day 28, there were 73 deaths (63%) in the placebo group and 60 deaths
(53%) in the corticosteroid group. The median time to death was 12 days in
the placebo group and 24 days in the corticosteroid group. The HR estimated
using a Cox model was 0.67 (95% CI, 0.47-0.95; P
= .02; Figure 2A). The number of
patients needed to treat to save 1 additional life at day 28 is 7 (95% CI,
4-49).

Responders

At day 28, there were 18 deaths (53%) in the placebo group and 22 deaths
(61%) in the corticosteroid group. The median time to death was 14 days in
the placebo group and 16.5 days in the corticosteroid group. The proportionality
assumption was not supported for the Cox model and comparison of survival
distributions was performed using a log-rank test (P
= .81) (Figure 2B).

All Patients

At day 28, there were 91 deaths (61%) in the placebo group and 82 deaths
(55%) in the corticosteroid group. The median time to death was 13 days in
the placebo group and 19.5 days in the corticosteroid group. The HR estimated
using a Cox model was 0.71 (95% CI, 0.53-0.97; P
= .03) (Figure 2C). The number of
patients needed to treat to save 1 additional life at day 28 is 8 (95% CI,
5-81).

Mortality Rates

Nonresponders

As mentioned above, at day 28, there were 73 deaths (63%) in the placebo
group and 60 deaths (53%) in the corticosteroid group (RR, 0.83; 95% CI, 0.66-1.04;
adjusted OR, 0.54; 95% CI, 0.31-0.97; P = .04). There
were 81 deaths (70%) in the placebo group and 66 deaths (58%) in the corticosteroid
group at the end of ICU stay (RR, 0.82; 95% CI, 0.68-1.00; adjusted OR, 0.50;
95% CI, 0.28-0.89; P = .02). A similar significant
difference was observed at the end of hospital stay. There were 88 deaths
(77%) in the placebo group and 77 deaths (68%) in the corticosteroid group
after 1 year of follow-up (RR, 0.88; 95% CI, 0.75-1.04; adjusted OR, 0.57;
95% CI, 0.31-1.04; P = .07) (Table 4).

Responders

There was no significant effect of corticosteroids on 28-day, ICU, hospital,
and 1-year mortality rates in responders (Table 4).

The median time to vasopressor therapy withdrawal was 10 days in the
placebo group and 7 days in the corticosteroid group. The HR estimated using
a Cox model was 1.91 (95% CI, 1.29-2.84; P = .001)
(Figure 3A). At day 28, vasopressor
therapy had been withdrawn in 46 patients (40%) in the placebo group and in
65 patients (57%) in the corticosteroid group.

Responders

The median time-to-vasopressor-therapy withdrawal was 7 days in the
placebo group and 9 days in the corticosteroid group. The proportionality
assumption was not supported for the Cox model and comparison of time-to-vasopressor-therapy
withdrawal distributions was performed using a log-rank test (P = .49, Figure 3B). At day
28, vasopressor therapy had been withdrawn in 18 patients (53%) in the placebo
group and in 18 patients (50%) in the corticosteroid group.

All Patients

The median time to vasopressor therapy withdrawal was 9 days in the
placebo group and 7 days in the corticosteroid group. The HR estimated using
a Cox model was 1.54 (95% CI, 1.10-2.16; P = .01; Figure 3C). At day 28, vasopressor therapy
had been withdrawn in 64 patients (43%) in the placebo group and in 83 patients
(55%) in the corticosteroid group.

Adverse Events

There were no significant differences between the 2 groups in the rates
of adverse events possibly related to corticosteroids or vasopressors, or
related to ICU invasive procedures (Table
5).

COMMENT

We found that a 7-day replacement therapy with hydrocortisone (50 mg
intravenous bolus every 6 hours) and fludrocortisone (50 µg tablet once
daily) significantly reduced 28-day mortality and duration of vasopressor
administration in all patients with septic shock, in particular those with
relative adrenal insufficiency. In addition, among the latter, corticosteroid
therapy significantly reduced mortality during both ICU and hospital stays,
and tended to reduce 1-year mortality. Our results indicate that, in this
population, 1 additional life could be saved at day 28 for every 7 patients
treated with corticosteroids. Replacement therapy had no significant effect
on the same variables in patients who had septic shock without relative adrenal
insufficiency. If the power to detect differences in responders was lower
than that in nonresponders due to the lower proportion of responders, it should
be observed that no tendency toward efficacy (or deleterious effect) was observed
in responders for any of the above mentioned variables. These results confirm
the hypothesis on which the study was planned that patients with septic shock
with relative adrenal insufficiency could benefit from replacement therapy.

Our results are consistent with a study of healthy volunteers challenged
with endotoxin27 and with 2 studies of patients
with septic shock,12,13 that showed
that low doses of hydrocortisone can restore vascular responsiveness to catecholamines.
Our results are also consistent with those of 2 small trials showing that
replacement therapy with hydrocortisone reduces the time-to-vasopressor-therapy
withdrawal in septic shock.14,15
Finally, our study establishes that a short corticotropin test performed at
early onset of septic shock is useful for identifying patients that could
most benefit from replacement therapy with corticosteroids. However, it has
to be stressed that the time required to obtain the results largely depends
on the method used to measure cortisol (eg, enzymatic method, radioimmunoassay)
and therefore that treatment should be started as soon as the test has been
completed.

The sample size was calculated to detect a difference of 20% between
the 2 groups of nonresponders on the 28-day mortality rate using a 1-sided
formulation. Such a formulation was chosen because the preliminary reports
that were available at the planning phase of the study22,23
had shown that for several days patients tolerated well 200 to 300 mg of hydrocortisone
daily, and we had no interest in formally demonstrating a hypothetical deleterious
effect of corticosteroids. However, as recommended by the 9th International
Conference on Harmonization, at the time of analysis, all tests were performed
using a 2-sided formulation and all reported P values
were 2-sided. The sample size was also computed based on the assumptions of
a mortality rate of 95% in the nonresponder placebo subgroup and a frequency
of nonresponders of 40% in the population of patients with septic shock. In
fact, the mortality rate in the nonresponder placebo subgroup (63%) was much
lower than expected compared with the reports that were available at the planning
phase of the study7,22 and with
the hypothesis that patients with adrenal insufficiency would very likely
die without hormone replacement. Conversely, the proportion of nonresponders
(77%) was much higher than expected and the resulting increase in the sample
size of nonresponders (from 108 to 229) may have favored the detection of
a lower difference (10%) than expected between the 2 groups.

Several differences between the design of this positive study and previous
negative studies28- 33
deserve comment. First, our trial was focused on a very specific population
who were presumed to benefit from corticosteroids because of relative adrenal
insufficiency. Second, low doses of a combination of the natural hormone hydrocortisone
and fludrocortisone were used (as recommended to treat adrenal insufficiency)16 rather than high doses of a synthetic glucocorticoid
compound. The addition of fludrocortisone to hydrocortisone was justified
because primary adrenal insufficiency could not be ruled out16
since it has been shown that 40% to 65% of critically ill patients have high-plasma
renin activity and low-plasma aldosterone concentrations.34,35
Moreover, in situations that require high amounts of active glucocorticoid,
the reduction of fludrocortisone to cortisol can serve as a second source
of cortisol in addition to that of adrenal glands.36
Third, patients were treated for a longer time (ie, 7 days) than those treated
in previous trials. Indeed, recent work in healthy volunteers challenged with
endotoxin37 and in patients with septic shock23,38 have shown that short courses of
corticosteroid treatment may be followed by a rebound of the systemic inflammatory
response.

In conclusion, in catecholamine-dependent septic shock patients, particularly
those with relative adrenal insufficiency, a 7-day treatment with the combination
of hydrocortisone and fludrocortisone is safe and associated with a significant
reduction in short-term and long-term mortality. In practice, we suggest that
all patients with catecholamine-dependent septic shock should be given the
combination of hydrocortisone and fludrocortisone as soon as a short corticotropin
stimulation test is performed. When the results of the test are available,
treatment may be withdrawn in responders and continued up to 7 days in nonresponders.
Further studies are required to better determine the optimal dose and duration
of corticosteroids to be given in this setting. The interest of a replacement
therapy with corticosteroids in patients with septic shock without relative
adrenal insufficiency deserves additional investigation.